Background: In patients with bipolar disorder, medication is effective in preventing relapses. Unfortunately, adherence to treatment in bipolar disorder, as in other chronic or recurrent conditions, is not optimal. Estimates of nonadherence to prescribed treatment range from 30% to 60% in epidemiological studies, and are at around 30% in clinical trials. Adherence to treatment is a potent predictor of effectiveness, both in clinical trials and cohort studies, therefore is a very relevant area of investigation. This study will try to show a picture of the real life care where adherence is influenced by a wide range of variables. Methods: Prospective, observational, multicenter study in 650 adult patients with bipolar disorder, who had to initiate or change their treatment regimen, observed for 1 year. Adherence was measured by the Simplified Medication Adherence Questionnaire (SMAQ). Additional variables: Symptom severity, Montgomery-Åsberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), Clinical Global Impression–Bipolar Disorder (CGI-BD), the Drug Attitude Inventory score (DAI-30), and quality of life (EuroQoL 5 Dimensions). The variables were recorded every 3 months for the next year. Results: Most subjects were out-patients (77.1%), female (58.8%), aged 31–50 years (50.1%) and overweight (41.8%) or obese (28.7%); 67.4% had type I bipolar disorder and 66.8% had depressive or mixed symptoms. Adherence was 39.9% at baseline (and increased up to 67.0% at completion. The main predictors of nonadherence were alcohol consumption, severe bipolar symptoms, young age at time of first treatment, negative attitude towards treatment. Conclusions: The patient population of this observational trial was representative of the patients changing their therapy for bipolar disorder seen in clinical practice in Italy. Lack of adherence to pharmacotherapy for bipolar disorder is a serious issue, which is more likely to arise in alcohol users and patients with severe symptoms, negative attitude towards medication and/or initiation of treatment early in life. The findings could lead to a more adequate approach of adherence in patients with bipolar disorders.